Denisovan genomes may clarify evolution

GENETICS

Updated 10:28 pm, Saturday, September 15, 2012

A cave in Siberia is the source of Denisova remains, which have led to clues about human evolution.

A cave in Siberia is the source of Denisova remains, which have led to clues about human evolution.

Photo: Johannes Krause, New York Times

Denisovan genomes may clarify evolution

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Los Angeles -- Our ancestors didn't walk alone: Neanderthals and other ancient peoples shared Earth with them tens of thousands of years ago.

Now, using new technology, scientists have sequenced with high precision the genome of one of those close but little-known relatives: an extinct people known as the Denisovans, who lived in and around modern-day Siberia.

The Denisovan genome, reported online Thursday in the journal Science, was derived from tiny quantities of shredded DNA extracted from a finger bone found in a Russian cave in 2008, as well as a tooth found later.

What is striking, scientists said, is that it is every bit as detailed as a sequence generated with a fresh blood or saliva sample from someone alive today.

Analysis of the genome and comparisons with ours and the Neanderthals' will offer insights into the history of Homo sapiens - who we mated with, where and when - as well as the unique genetic changes that make modern humans who they are, scientists said.

Study leader Svante Paabo, a pioneer in decoding ancient genomes, said it would take biologists decades to understand the meaning of all these tiny differences.

"Many of them may have no function - but among them will undoubtedly hide some crucial changes that are essential for what made modern human history possible," said Paabo, director of the department of evolutionary genetics at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany.

Already, he and his coauthors have highlighted several intriguing genetic differences between modern humans and our primitive relatives that could be significant, including genes involved in wiring the brain and ones that are known to be linked to autism.

Their analysis also suggests that the Denisovans had dark skin, brown hair and brown eyes, but scientists can't yet say much more than that about their appearance.

The advance hinged on new techniques designed to investigate scant and highly degraded genetic material found in fossils. Their application to these and other specimens promises to draw back the curtain on our species' complicated and much-debated history, said John Hawks, a paleoanthropologist at University of Wisconsin, Madison, who wasn't involved in the study.

Very likely, modern humans have other undiscovered ancient relatives whose fossilized bones are waiting to give up their secrets.

"It's got to be just the beginning," Hawks said.

The part of the world where the Denisovan fossils were discovered could contain a particularly rich trove of archaic humans, said Michelle Glantz, a biological anthropologist at Colorado State University in Fort Collins, who wasn't involved in the study.

Among the other intriguing finds from Central Asia is a fossil from Uzbekistan with a Neanderthal-like inner ear and a cranium resembling a modern human's. But it will take a lot more than DNA data to piece together the picture there, she said.

The evolutionary path of humans is in many respects still mysterious, and the exact timing of events is uncertain. But the story goes something like this: Ancestors of humans emerged in Africa and migrated out to the rest of the world in several successive waves.

The first globe-trotter was Homo erectus, whose trek began 1 million to 2 million years ago. Then came the ancestor of the Neanderthals and Denisovans, who left Africa as far back as 800,000 years ago and replaced or interbred with descendants of Homo erectus.

The third wave of people, Homo sapiens, left Africa perhaps 100,000 years ago and sometimes mated with the Neanderthals and Denisovans they encountered. The result is you and me and everyone else on the planet.

The new genome gives scientists a sense of just how much of our genomes we owe to our extinct relatives. About 3 percent to 5 percent of the DNA in people native to Papua New Guinea, Australia, the Philippines and other islands nearby came from Denisovans, the study found, confirming reports based on a draft version of the Denisovan genome. The authors of the study didn't find any significant contribution of Denisovans to the DNA of people from mainland Eurasia, however.

The new gene-sequencing techniques also allowed scientists to calculate more precisely how much of modern humans' DNA came not from Denisovans, but from Neanderthals. They found, to their puzzlement, that Native Americans and people in East Asia have more Neanderthal DNA than do people whose ancestors are from Europe, where most Neanderthals lived.

The study authors don't know how this happened, but they have theories. Perhaps Neanderthals bred with modern humans during more than one time and place, which would overturn theories that DNA mixing occurred only in the period when modern humans first came out of Africa and met the Neanderthals, presumably in the Middle East.

Or maybe a later influx of modern humans into Europe essentially diluted out the Neanderthal DNA in the people living there.

In another first, the authors used the DNA sequence to estimate the age of the Denisovan pinky finger bone.

They started by counting up all the tiny genetic changes that have accrued in the genomes of modern humans and Denisovans since our lineage diverged from that of chimpanzees 6.5 million years ago. Then they compared the two numbers.

Genetic changes build up regularly through the ages, like the ticking of a clock, so the tally allows scientists to estimate the passage of time. Not surprisingly, the Denisovan sample had amassed fewer changes than its human counterparts. From the difference, the authors estimated that our ancient relative, believed to be a female child, met her end somewhere between 74,000 and 82,000 years ago.

The authors used the same approach to estimate how long ago our lineage branched away from the line that led to the Denisovans and Neanderthals. It happened somewhere between 170,000 and 700,000 years ago, they concluded.

The range is broad because the modern DNA revolution has overturned notions of how fast the internal genetic clock is ticking, said study coauthor Matthias Meyer.

The high-precision Denisovan genome, which was sequenced 30 times over to ramp up accuracy, is the result of a complete overhaul in the approach toward processing and analyzing DNA from fossils.

Until now, "all forensics and ancient DNA work were based on protocols that were originally developed for modern DNA," Meyer said. And yet the materials are in very different states, with old DNA existing in tiny pieces and trace amounts, while modern DNA is contained in plentiful long strands.

The new technique exploited the fact that DNA is composed of two strands wound together in a double helix; by separating them and sequencing both, the team multiplied the amount of scarce material available for analysis. Bits of synthetic DNA were attached to the ends of each fragment to allow them to be copied and read, said Meyer, who developed the method in Paabo's lab.

The scientists perfected their methods on fossil bones from cave bears because DNA from human fossils was too precious to be squandered on trial runs. Indeed, the Denisovan material is so scant that it cannot even be carbon-dated.

Paabo said his team is eager to use the new method to sequence DNA from other intriguing fossils. First up is the Neanderthal genome, which exists only in rough draft form now. It should be complete within a year.